mARC1 in MASLD: Modulation of lipid accumulation in human hepatocytes and adipocytes.

BACKGROUND: Mutations in the gene MTARC1 (mitochondrial amidoxime-reducing component 1) protect carriers from metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. MTARC1 encodes the mARC1 enzyme, which is localized to the mitochondria and has no known MASH-relevant molecular function. Our studies aimed to expand on the published human genetic mARC1 data and to observe the molecular effects of mARC1 modulation in preclinical MASH models. METHODS AND RESULTS: We identified a novel human structural variant deletion in MTARC1, which is associated with various biomarkers of liver health, including alanine aminotransferase levels. Phenome-wide Mendelian Randomization analyses additionally identified novel putatively causal associations between MTARC1 expression, and esophageal varices and cardiorespiratory traits. We observed that protective MTARC1 variants decreased protein accumulation in in vitro overexpression systems and used genetic tools to study mARC1 depletion in relevant human and mouse systems. Hepatocyte mARC1 knockdown in murine MASH models reduced body weight, liver steatosis, oxidative stress, cell death, and fibrogenesis markers. mARC1 siRNA treatment and overexpression modulated lipid accumulation and cell death consistently in primary human hepatocytes, hepatocyte cell lines, and primary human adipocytes. mARC1 depletion affected the accumulation of distinct lipid species and the expression of inflammatory and mitochondrial pathway genes/proteins in both in vitro and in vivo models. CONCLUSIONS: Depleting hepatocyte mARC1 improved metabolic dysfunction-associated steatotic liver disease-related outcomes. Given the functional role of mARC1 in human adipocyte lipid accumulation, systemic targeting of mARC1 should be considered when designing mARC1 therapies. Our data point to plasma lipid biomarkers predictive of mARC1 abundance, such as Ceramide 22:1. We propose future areas of study to describe the precise molecular function of mARC1, including lipid trafficking and subcellular location within or around the mitochondria and endoplasmic reticulum.

Online survey exploring researcher experiences of research funding processes in the UK: the effort and burden of applying for funding and fulfilling reporting requirements.

OBJECTIVE: To explore researchers' experiences of funding processes, the effort and burden involved in applying for funding, obtaining funding and/or fulfilling reporting requirements with a UK health and social care research funder. DESIGN/SETTING: A cross-sectional online survey study with open (free-text) and closed questions (August to November 2021). PARTICIPANTS: Researchers with experience of applying for/obtaining funding and/or experience of fulfilling reporting requirements for UK health and social care research funded between January 2018 and June 2021. RESULTS: The survey was completed by 182 researchers, of which 176 had experience with applying for/obtaining funding, and 143 had experience with fulfilling reporting requirements during the timeframe. The majority of the 176 respondents (58%) completed between 7 and 13 key processes in order to submit an application and 69% felt that it was critically important to undertake these key processes. Respondents (n=143) reported submitting an average of 17 reports as part of research monitoring to a range of organisations (eg, funders, Higher Education Institutions). However, only 33% of respondents felt it was critically important to provide the requested reporting information to the different organisations. Thematic analysis of free-text questions on application and reporting identified themes relating to process inefficiencies including streamlining and alignment of systems, lack of understanding of processes including a need for improved communication and feedback from organisations with clear explanations about what information is needed, when and why, the support required by respondents and the time, effort and impact on workload and well-being. CONCLUSIONS: Through this study, we were able to identify funding processes that are considered by some to be effortful, but necessary, as well as those that were perceived as unnecessary, complex and repetitive, and may waste some researchers time and effort and impact on well-being. Possible solutions to increase efficiency and enhance value in these processes were identified.

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination.

Kinetic studies on the intramolecular hydroamination of protected variants of 2,2-diphenylpent-4-en-1-amine were carried out under a variety of conditions with cationic gold catalysts supported by phosphine ligands. The impact of ligand on gold, protecting group on nitrogen, and solvent and additive on reaction rates was determined. The most effective reactions utilized more Lewis basic ureas, and more electron-withdrawing phosphines. A DCM/alcohol cooperative effect was quantified, and a continuum of isotope effects was measured with low KIE's in the absence of deuterated alcoholic solvent, increasing to large solvent KIE's when comparing reactions in pure MeOH to those in pure MeOH-d4. The effects are interpreted both within the context of a classic gold π-activation/protodeauration mechanism and a general acid-catalyzed mechanism without intermediate gold alkyls.

Postoperative Recovery of Quality-of-Life Following Ureteroscopy for Nephrolithiasis: The Impact on Pain Intensity and Interference and the Ability to Participate in Social Roles.

OBJECTIVE: To prospectively capture patient-reported outcomes to assess the recovery profile of ureteroscopy (URS). MATERIALS AND METHODS: Adults undergoing URS for renal/ureteral stones were eligible for inclusion (11/2020-8/2022). Patients prospectively completed PROMIS - Pain Intensity, - Pain Interference, and - Ability to participate in social roles and activities in-person preoperatively (POD 0) and via email on POD 1, 7, 14, and 30. Scores are reported as T-scores (normalized to U.S. population, mean=50) with a change of 5 (0.5 SD) considered clinically significant. RESULTS: One hundred and seventy-eight participants enrolled at POD 0 (POD 1 =87, POD 7 =83, POD 14 =70, POD30 =67). There was a worsening of quality of life from day 0 to day 1 and day 0 to 7. All dimensions then improved with an increase in scores from day 0 to day 14 and day 0 to day 30. On multivariable analysis, the presence of a preoperative ureteral stent (OR 0.14) and use of semirigid URS (OR 0.33) were associated with a reduced odds for severe pain interference at day 1. The use of semirigid URS (OR 0.20) was associated with a reduced odds for severe worsening in the ability to participate in social roles at day 1. CONCLUSION: Ability to participate in social roles declines immediately postoperatively, while pain intensity and interference sharply increase. There is a gradual improvement until POD 30. Findings suggest preoperative stents may influence postoperative recovery. Results offer meaningful insight to assist in counseling and setting expectation for patients postoperatively.

The association of resilience and positive mental health in systemic sclerosis: A Scleroderma Patient-centered Intervention Network (SPIN) cohort cross-sectional study.

OBJECTIVE: A previous study using Scleroderma Patient-centered Intervention Network (SPIN) Cohort data identified five classes of people with systemic sclerosis (also known as scleroderma) based on patient-reported somatic (fatigue, pain, sleep) and mental health (anxiety, depression) symptoms and compared indicators of disease severity between classes. Across four classes ("low", "normal", "high", "very high"), there were progressively worse somatic and mental health outcomes and greater disease severity. The fifth ("high/low") class, however, was characterized by high disease severity, fatigue, pain, and sleep but low mental health symptoms. We evaluated resilience across classes and compared resilience between classes. METHODS: Cross-sectional study. SPIN Cohort participants completed the 10-item Connor-Davidson-Resilience Scale (CD-RISC) and PROMIS v2.0 domains between August 2022 and January 2023. We used latent profile modeling to identify five classes as in the previous study and multiple linear regression to compare resilience levels across classes, controlling for sociodemographic and disease variables. RESULTS: Mean CD-RISC score (N = 1054 participants) was 27.7 (standard deviation = 7.3). Resilience decreased progressively across "low" to "normal" to "high" to "very high" classes (mean 4.7 points per step). Based on multiple regression, the "high/low" class exhibited higher resilience scores than the "high" class (6.0 points, 95% confidence interval [CI] 4.9 to 7.1 points; standardized mean difference = 0.83, 95% CI 0.67 to 0.98). CONCLUSIONS: People with worse disease severity and patient-reported outcomes reported substantially lower resilience, except a class of people with high disease severity, fatigue, pain, and sleep disturbance but positive mental health and high resilience.

Ultra-low dose chest CT with silver filter and deep learning reconstruction significantly reduces radiation dose and retains quantitative information in the investigation and monitoring of lymphangioleiomyomatosis (LAM).

PURPOSE: Frequent CT scans to quantify lung involvement in cystic lung disease increases radiation exposure. Beam shaping energy filters can optimize imaging properties at lower radiation dosages. The aim of this study is to investigate whether use of SilverBeam filter and deep learning reconstruction algorithm allows for reduced radiation dose chest CT scanning in patients with lymphangioleiomyomatosis (LAM). MATERIAL AND METHODS: In a single-center prospective study, 60 consecutive patients with LAM underwent chest CT at standard and ultra-low radiation doses. Standard dose scan was performed with standard copper filter and ultra-low dose scan was performed with SilverBeam filter. Scans were reconstructed using a soft tissue kernel with deep learning reconstruction (AiCE) technique and using a soft tissue kernel with hybrid iterative reconstruction (AIDR3D). Cyst scores were quantified by semi-automated software. Signal-to-noise ratio (SNR) was calculated for each reconstruction. Data were analyzed by linear correlation, paired t-test, and Bland-Altman plots. RESULTS: Patients averaged 49.4 years and 100% were female with mean BMI 26.6 ± 6.1 kg/m2. Cyst score measured by AiCE reconstruction with SilverBeam filter correlated well with that of AIDR3D reconstruction with standard filter, with a 1.5% difference, and allowed for an 85.5% median radiation dosage reduction (0.33 mSv vs. 2.27 mSv, respectively, p < 0.001). Compared to standard filter with AIDR3D, SNR for SilverBeam AiCE images was slightly lower (3.2 vs. 3.1, respectively, p = 0.005). CONCLUSION: SilverBeam filter with deep learning reconstruction reduces radiation dosage of chest CT, while maintaining accuracy of cyst quantification as well as image quality in cystic lung disease. CLINICAL RELEVANCE STATEMENT: Radiation dosage from chest CT can be significantly reduced without sacrificing image quality by using silver filter in combination with a deep learning reconstructive algorithm. KEY POINTS: • Deep learning reconstruction in chest CT had no significant effect on cyst quantification when compared to conventional hybrid iterative reconstruction. • SilverBeam filter reduced radiation dosage by 85.5% compared to standard dose chest CT. • SilverBeam filter in coordination with deep learning reconstruction maintained image quality and diagnostic accuracy for cyst quantification when compared to standard dose CT with hybrid iterative reconstruction.

Compliance of Adolescent Friendly Health Clinics with National and International Standards: Quantitative findings from the i-Saathiya study.

OBJECTIVE: Indian adolescents experience several health challenges requiring acceptable, equitable, appropriate and effective healthcare services. Our objective was to assess the compliance of Adolescent Friendly Health Clinics (AFHCs) in two of India's largest states, using both national benchmarks (under Rashtriya Kishor Swasthya Karyakram-RKSK) and global standards (by WHO). DESIGN: Cross-sectional study comprising structured observations and interactions (November 2021 to June 2022). SETTING: Fourteen AFHCs across all levels of health system were included from two districts of Maharashtra (n=8) and Madhya Pradesh (n=6). These AFHCs were observed using checklist, and few items of checklist were verified by interactions with AFHC's health workers (medical officers/auxillary nurse midwives/counsellors) handlings adolescents. The developed checklist included 57 items based on adapted global standards and 25 items using national benchmarks. RESULT: High compliance of AFHCs with RKSK's benchmarks was attributed to various items including the accessibility through local transport (n=14, 100%), clean surroundings (n=11, 78.5%), presence of signage (n=10, 71.4%), convenient operating days and time (n=11, 78.5%), and secure storage of records (n=13, 92.9%). Concurrently, items that showed low compliance encompassed, the availability of Information, Education and communication (IEC) resources, which were deficient in 57.1% of AFHCs (n=8). Similarly, designated areas for clinical services (n=10, 71.4%) and commodity disbursement (n=9, 64.3%) lacked in more than half of the recruited AFHCs. Additionally, lack of guidelines for referrals (n=13, 92.9%), as well as standard operating procedures to ensure equity, non-judgemental attitude, competence, confidentiality and referral as per WHO standards. CONCLUSION: Evidence spotlights the strengths and gaps in AFHCs, aligning with, government's priorities on adolescent health. Addressing the identified gaps is crucial to creating healthcare facilities that are adolescent-friendly, easily accessible and effectively navigate adolescent health challenges. This concerted effort would contribute to their development and transformation, playing a pivotal role in India's progress.

Moderators of Loneliness Trajectories in People with Systemic Sclerosis During the COVID-19 Pandemic: A SPIN COVID-19 Cohort Longitudinal Study.

BACKGROUND: Many individuals with systemic sclerosis (SSc) are at heightened risk for COVID-19 related morbidity and isolation due to interstitial lung disease, frailty, and immunosuppressant use. Minimal research has explored loneliness predictors in individuals with chronic illnesses during COVID-19. This study evaluated moderators of loneliness trajectories in individuals with SSc during COVID-19. METHODS: Longitudinal data were analyzed across 30 timepoints from April 2020 to May 2022 from 775 adults in the Scleroderma Patient-centered Intervention Network (SPIN) COVID-19 Cohort. Hierarchical linear modeling evaluated cross-level moderators of loneliness trajectories, including marital status, baseline number of household members, number of virtual or telephone one-on-one or virtual group conversations, number of hours spent enjoying in-person household conversations or activities, and satisfaction with quality of in-person household conversations (all in the past week). Level-1 moderation analyses assessed effects of conversation, activity, and satisfaction means and slopes over time. RESULTS: Baseline values were not statistically significant moderators of loneliness trajectories. Higher mean (averaged over time) virtual or telephone one-on-one and in-person household conversations, in-person household activity, and in-person household conversation satisfaction were associated with lower loneliness trajectories (ps < .05). The relationship between in-person household conversation satisfaction and loneliness trajectory was statistically significantly but minimally attenuated over time (p < .001). CONCLUSIONS: For people with SSc, higher mean conversation, activity, and satisfaction variables were associated with lower levels of loneliness during the pandemic, but changes in these social variables were generally not predictive of changes in loneliness.

Role of histone variants H2BC1 and H2AZ.2 in H2AK119ub nucleosome organization and Polycomb gene silencing.

Ubiquitination of histone H2A at lysine 119 residue (H2AK119ub) plays critical roles in a wide range of physiological processes, including Polycomb gene silencing 1,2 , replication 3-5 , DNA damage repair 6-10 , X inactivation 11,12 , and heterochromatin organization 13,14 . However, the underlying mechanism and structural basis of H2AK119ub remains largely elusive. In this study, we report that H2AK119ub nucleosomes have a unique composition, containing histone variants H2BC1 and H2AZ.2, and importantly, this composition is required for H2AK119ub and Polycomb gene silencing. Using the UAB domain of RSF1, we purified H2AK119ub nucleosomes to a sufficient amount and purity. Mass spectrometry analyses revealed that H2AK119ub nucleosomes contain the histone variants H2BC1 and H2AZ.2. A cryo-EM study resolved the structure of native H2AK119ub nucleosomes to a 2.6A resolution, confirming H2BC1 in one subgroup of H2AK119ub nucleosomes. Tandem GST-UAB pulldown, Flag-H2AZ.2, and HA-H2BC1 immunoprecipitation revealed that H2AK119ub nucleosomes could be separated into distinct subgroups, suggesting their composition heterogeneity and potential dynamic organization. Knockout or knockdown of H2BC1 or H2AZ.2 reduced cellular H2AK119ub levels, establishing H2BC1 and H2AZ.2 as critical determinants of H2AK119ub. Furthermore, genomic binding profiles of H2BC1 and H2AZ.2 overlapped significantly with H2AK119ub binding, with the most significant overlapping in the gene body and intergenic regions. Finally, assays in developing embryos reveal an interaction of H2AZ.2, H2BC1, and RING1A in vivo . Thus, this study revealed, for the first time, that the H2AK119ub nucleosome has a unique composition, and this composition is required for H2AK119ub and Polycomb gene silencing.

The estimated health impact of alcohol interventions in New Zealand: A modelling study.

AIMS: To estimate the health impacts of key modelled alcohol interventions among Maori (indigenous peoples) and non-Maori in New Zealand (NZ). DESIGN: Multi-stage life-table intervention modelling study. We modelled two scenarios: (1) business-as-usual (BAU); and (2) an intervention package scenario that included a 50% alcohol tax increase, outlet density reduction from 63 to five outlets per 100 000 people, outlet hours reduction from 112 to 50 per week and a complete ban on all forms of alcohol marketing. SETTING AND PARTICIPANTS: The model's population replicates the 2018 NZ population by ethnicity (Maori/non-Maori), age and sex. MEASUREMENTS: Alcohol consumption was estimated using nationally representative survey data combined with sales data and corrected for tourist and unrecorded consumption. Disease incidence, prevalence and mortality were calculated using Ministry of Health data. We used dose-response relationships between alcohol and illness from the 2016 Global Burden of Disease study and calculated disability rates for each illness. Changes in consumption were based on the following effect sizes: total intervention package [-30.3%, standard deviation (SD) = 0.02); tax (-7.60%, SD = 0.01); outlet density (-8.64%, SD = 0.01); outlet hours (-9.24%, SD = 0.01); and marketing (-8.98%, SD = 0.02). We measured health gain using health-adjusted life years (HALYs) and life expectancy. FINDINGS: Compared with the BAU scenario, the total alcohol intervention package resulted in 726 000 [95% uncertainty interval (UI) = 492 000-913 000] HALYs gained during the life-time of the modelled population. Maori experienced greater HALY gains compared with non-Maori (0.21, 95% UI = 0.14-0.26 and 0.16, 95% UI = 0.11-0.20, respectively). When modelled individually, each alcohol intervention within the intervention package produced similar health gains (~200 000 HALYs per intervention) owing to the similar effect sizes. CONCLUSIONS: Modelled interventions for increased alcohol tax, reduced availability of alcohol and a ban on alcohol marketing among Maori and non-Maori in New Zealand (NZ) suggest substantial population-wide health gains and reduced health inequities between Maori and non-Maori.

Food tax policies in Pacific Island Countries and Territories: systematic policy review.

OBJECTIVE: To systematically identify and review food taxation policy changes in Pacific Island Countries and Territories (PICTs). DESIGN: Food taxation polices, regarding excise taxes and tariffs applied from 2000 to 2020 in twenty-two PICTs, and their key characteristics were reviewed. The search was conducted using databases, government legal repositories and broad-based search engines. Identified documents for screening included legislation, reports, academic literature, news articles and grey literature. Key informants were contacted from each PICT to retrieve further data and confirm results. Results were analysed by narrative synthesis. SETTING: Noncommunicable diseases (NCD) are the leading cause of premature death in PICTs and in many jurisdictions globally. An NCD crisis has been declared in the Pacific, and food taxation policy has been recommended to address the dietary risk factors associated with. Progress is unclear. RESULTS: Of the twenty-two PICTs included in the study, fourteen had food taxation policies and five introduced excise taxes. Processed foods, sugar and salt were the main target of excise taxes. A total of eighty-four food taxation policy changes were identified across all food groups. There was a total of 279 taxes identified by food group, of which 85 % were tariffs and 15 % were excise taxes. Individual tax rates varied substantially. The predominant tax design was ad valorem, and this was followed by volumetric. CONCLUSIONS: A quarter of PICTs have introduced food excise taxes from 2000 to 2020. Further excise taxes, specifically tiered or nutrient-specific designs, could be introduced and more systematically applied to a broader range of unhealthy foods.

Sexual, reproductive and mental health among young men (10-24) in low-and-middle income countries: a scoping review.

Background: The relationship between SRH and mental health among men is not well documented, especially in the 10-24 age group. This scoping review aimed to investigate what is known about the association between SRH and mental health among young men (10-24) in LMICs. Methods: Embase, APA PsycInfo, MEDLINE(R) ALL, ASSIA and the Cochrane Library of Database of Systematic Reviews were searched from the year of establishment up to August 2022. The review was reported using the PRISMA-ScR checklist. Results: A total of (n = 2636) studies were identified from the five databases. After the completion of screening, only ten studies (n = 8 cross-sectional, n = 1 mixed methods and n = 1 qualitative) met the eligibility criteria and were included in the review. The findings suggest that there is a reciprocal relationship between mental health and SRH. Sperm concentration and total sperm count were found to be lower in depressed men. Poor mental health was associated with early sexual debut, higher rates of sexual activity and an increased number of sexual partners. Poor mental health was also found among men who had sex with men (MSM). In addition, we found a relationship between sexual abuse, sexual coercion and poor mental health. Conclusion: The findings of this unique study indicate that poor mental health is associated with poor SRH outcomes and vice versa among young men (10-24) living in LMICs. However, further research will be needed to establish the temporal relationship between SRH and mental health outcomes.

The post-award effort of managing and reporting on funded research: a scoping review.

INTRODUCTION: Reporting is a mechanism for funding organisations to monitor and manage the progress, outputs, outcomes, and impacts of the research they fund. Inconsistent approaches to reporting and post-award management, and a growing demand for research information, can lead to perception of unnecessary administrative effort that impacts on decision-making and research activity. Identifying this effort, and what stakeholders see as unmet need for improvement, is crucial if funders and Higher Education Institutions (HEIs) are to streamline their practices and provide better support with reporting activities. In this review, we summarise the processes in post-award management, compare current practices, and explore the purpose of collecting information on funded research. We also identify areas where unnecessary effort is perceived and improvement is needed, using previously reported solutions to inform recommendations for funders and HEIs. METHODS: We conducted a scoping review of the relevant research and grey literature. Electronic searches of databases, and manual searches of journals and funder websites, resulted in inclusion of 52 records and 11 websites. Information on HEI and funder post-award management processes was extracted, catalogued, and summarised to inform discussion. RESULTS: Post-award management is a complex process that serves many purposes but requires considerable effort, particularly in the set up and reporting of research. Perceptions of unnecessary effort stem from inefficiencies in compliance, data management and reporting approaches, and there is evidence of needed improvement in mechanisms of administrative support, research impact assessment, monitoring, and evaluation. Solutions should focus on integrating digital systems to reduce duplication, streamlining reporting methods, and improving administrative resources in HEIs. CONCLUSIONS: Funders and HEIs should work together to support a more efficient post-award management process. The value of research information, and how it is collected and used, can be improved by aligning practices and addressing the specific issues highlighted in this review.

An in-depth exploration of researcher experiences of time and effort involved in health and social care research funding in the UK: The need for changes.

The need to reform the way in which research is undertaken is clear, with reducing research bureaucracy and waste at the forefront of this issue for the UK government, funding organisations, higher education institutions and wider research community. The aim of this study was to describe researchers' experiences of the time, effort and burden involved in funding processes-namely applying for research funding and fulfilling reporting requirements. This was an in-depth qualitative study using semi-structured interviews with researchers who had experience applying for funding and/or completing reporting requirements for a UK health and social care research funder between January 2018 and June 2021. Following thematic analysis, five key themes were identified describing researcher experiences of key issues around time, efforts and burden associated with funding processes. These themes encompassed (1) issues with the current funding model for health and social care research, (2) time and effort involved in funding processes, (3) the need for a streamlined end-to-end process, (4) implications for work-life balance, and (5) addressing the need for better support and communication. The findings from this study describe researcher experiences of tasks in the research pathway that currently take considerable time and effort. It was clear that whilst some of this time and effort is considered necessary, some is exacerbated by inefficient and ineffective processes, such as perceived under-funding of research or lack of clarity with regards to funder expectations. This in turn contributes to unnecessary researcher burden, research waste and negative research culture. Better investment in health and social care research and in the researchers themselves who design and deliver the research, alongside improvements in transparency, streamlining and research support could ensure a more positive research culture, and improve the quality of funded research.

The use and acceptability of preprints in health and social care settings: A scoping review.

BACKGROUND: Preprints are open and accessible scientific manuscript or report that is shared publicly, through a preprint server, before being submitted to a journal. The value and importance of preprints has grown since its contribution during the public health emergency of the COVID-19 pandemic. Funders and publishers are establishing their position on the use of preprints, in grant applications and publishing models. However, the evidence supporting the use and acceptability of preprints varies across funders, publishers, and researchers. The scoping review explored the current evidence on the use and acceptability of preprints in health and social care settings by publishers, funders, and the research community throughout the research lifecycle. METHODS: A scoping review was undertaken with no study or language limits. The search strategy was limited to the last five years (2017-2022) to capture changes influenced by COVID-19 (e.g., accelerated use and role of preprints in research). The review included international literature, including grey literature, and two databases were searched: Scopus and Web of Science (24 August 2022). RESULTS: 379 titles and abstracts and 193 full text articles were assessed for eligibility. Ninety-eight articles met eligibility criteria and were included for full extraction. For barriers and challenges, 26 statements were grouped under four main themes (e.g., volume/growth of publications, quality assurance/trustworthiness, risks associated to credibility, and validation). For benefits and value, 34 statements were grouped under six themes (e.g., openness/transparency, increased visibility/credibility, open review process, open research, democratic process/systems, increased productivity/opportunities). CONCLUSIONS: Preprints provide opportunities for rapid dissemination but there is a need for clear policies and guidance from journals, publishers, and funders. Cautionary measures are needed to maintain the quality and value of preprints, paying particular attention to how findings are translated to the public. More research is needed to address some of the uncertainties addressed in this review.

Application of a life table approach to assess duration of BNT162b2 vaccine-derived immunity by age using COVID-19 case surveillance data during the Omicron variant period.

BACKGROUND: SARS-CoV-2 Omicron variants have the potential to impact vaccine effectiveness and duration of vaccine-derived immunity. We analyzed U.S. multi-jurisdictional COVID-19 vaccine breakthrough surveillance data to examine potential waning of protection against SARS-CoV-2 infection for the Pfizer-BioNTech (BNT162b) primary vaccination series by age. METHODS: Weekly numbers of SARS-CoV-2 infections during January 16, 2022-May 28, 2022 were analyzed by age group from 22 U.S. jurisdictions that routinely linked COVID-19 case surveillance and immunization data. A life table approach incorporating line-listed and aggregated COVID-19 case datasets with vaccine administration and U.S. Census data was used to estimate hazard rates of SARS-CoV-2 infections, hazard rate ratios (HRR) and percent reductions in hazard rate comparing unvaccinated people to people vaccinated with a Pfizer-BioNTech primary series only, by age group and time since vaccination. RESULTS: The percent reduction in hazard rates for persons 2 weeks after vaccination with a Pfizer-BioNTech primary series compared with unvaccinated persons was lowest among children aged 5-11 years at 35.5% (95% CI: 33.3%, 37.6%) compared to the older age groups, which ranged from 68.7%-89.6%. By 19 weeks after vaccination, all age groups showed decreases in the percent reduction in the hazard rates compared with unvaccinated people; with the largest declines observed among those aged 5-11 and 12-17 years and more modest declines observed among those 18 years and older. CONCLUSIONS: The decline in vaccine protection against SARS-CoV-2 infection observed in this study is consistent with other studies and demonstrates that national case surveillance data were useful for assessing early signals in age-specific waning of vaccine protection during the initial period of SARS-CoV-2 Omicron variant predominance. The potential for waning immunity during the Omicron period emphasizes the importance of continued monitoring and consideration of optimal timing and provision of booster doses in the future.

Can Peer-based Interventions Improve Adolescent Sexual and Reproductive Health Outcomes? An Overview of Reviews.

PURPOSE: An overview of reviews was conducted to summarize the evidence and synthesize the results from systematic reviews. METHODS: The Cochrane and Preferred Reporting Items for Overviews of Reviews reporting guidelines were followed and the protocol was registered. Electronic and manual searches were conducted to identify systematic reviews, published between January 1990 and July 2022. Studies with outcomes relating to all areas of adolescent sexual and reproductive health (SRH) (changes in knowledge, attitudes, beliefs, skills, and practices) were considered. The ROBIS (Risk of Bias in Systematic Reviews) tool was used to assess quality. RESULTS: A total 1849 articles were retrieved, and eight reviews met the inclusion criteria. Three of the eight reviews included meta-analyses. All three of these reviews demonstrated a significant improvement in HIV knowledge. One reported improved attitudes toward people living with HIV but none found any statistically significant effect on condom use or other SRH behaviors. The remaining five reviews included reports of positive individual study outcomes related to knowledge and attitudes and provided narrative syntheses with regard to recruitment, training, support, and participation of peers. Five of the eight reviews were judged to have a low risk of bias. DISCUSSION: Our overview demonstrates that peer-based interventions can improve SRH knowledge and attitudes. Evidence of their effectiveness in promoting healthier SRH behaviors is less certain. Any future studies need to investigate which adolescent health outcomes peer-based programs could reasonably be expected to improve using robust methodologies. Additionally, peers need to be meaningfully engaged and acknowledged as experience-based experts.

Metformin Disrupts Signaling and Metabolism in Fetal Hepatocytes.

Metformin is used by women during pregnancy to manage diabetes and crosses the placenta, yet its effects on the fetus are unclear. We show that the liver is a site of metformin action in fetal sheep and macaques, given relatively abundant OCT1 transporter expression and hepatic uptake following metformin infusion into fetal sheep. To determine the effects of metformin action, we performed studies in primary hepatocytes from fetal sheep, fetal macaques, and juvenile macaques. Metformin increases AMP-activated protein kinase (AMPK) signaling, decreases mammalian target of rapamycin (mTOR) signaling, and decreases glucose production in fetal and juvenile hepatocytes. Metformin also decreases oxygen consumption in fetal hepatocytes. Unique to fetal hepatocytes, metformin activates stress pathways (e.g., increased PGC1A gene expression, NRF-2 protein abundance, and phosphorylation of eIF2α and CREB proteins) alongside perturbations in hepatokine expression (e.g., increased growth/differentiation factor 15 [GDF15] and fibroblast growth factor 21 [FGF21] expression and decreased insulin-like growth factor 2 [IGF2] expression). Similarly, in liver tissue from sheep fetuses infused with metformin in vivo, AMPK phosphorylation, NRF-2 protein, and PGC1A expression are increased. These results demonstrate disruption of signaling and metabolism, induction of stress, and alterations in hepatokine expression in association with metformin exposure in fetal hepatocytes. ARTICLE HIGHLIGHTS: The major metformin uptake transporter OCT1 is expressed in the fetal liver, and fetal hepatic uptake of metformin is observed in vivo. Metformin activates AMPK, reduces glucose production, and decreases oxygen consumption in fetal hepatocytes, demonstrating similar effects as in juvenile hepatocytes. Unique to fetal hepatocytes, metformin activates metabolic stress pathways and alters the expression of secreted growth factors and hepatokines. Disruption of signaling and metabolism with increased stress pathways and reduced anabolic pathways by metformin in the fetal liver may underlie reduced growth in fetuses exposed to metformin.